Atorvastatin: Effective Therapy fora Broad Range of Dyslipidemias

NCEP Guidelines for LDL CholesterolNCEP. Circulation. 1994;89:1329-1445.

Major Studies Showing Relationship Between Cholesterol Levels and CHD Risk(Pre-Statin Studies)Study typeSize of cohortConclusionsEpidemiologic5127 (original)1% in cholesterol = 2% in CHD riskObservational361,662Continuous, graded association between cholesterol level and CHD risk starting at 180 mg/dLCastelli WP. Can J Cardiol. 1988;4(suppl A):5A-10A.Neaton JD, Wentworth D. Arch Intern Med. 1992;152:56-64.

Major Studies Showing a Beneficial Effect of Lipid-Lowering Therapy on CHD RiskLipid Research Clinics Program. JAMA. 1984;251:351-364.Frick MH et al. N Engl J Med. 1987;317:1237-1245.(Pre-Statin Studies)

4S ResultsScandinavian Simvastatin Survival Study Group. Lancet. 1994;344:1383-1389.*P=0.0003; P

WOSCOPS ResultsShepherd J et al. N Engl J Med. 1995;333:1301-1307.31% in risk of nonfatal MI or CHD death*33% in risk of definite and suspected CHD death22% in risk of all-cause mortalityChanges in lipids:20% in Total-C 5% in HDL-C26% in LDL-C12% in TG*P

CARE: Preliminary Results24% in risk of fatal CHD or nonfatal MI*25% in risk of fatal or nonfatal MI27% in need for coronary revascularizationChanges in lipids:20% in Total-C 5% in HDL-C28% in LDL-C14% in TGBraunwald E, Pfeffer MA, Sacks FM. Presented at the 45th ACC; March 26, 1996; Orlando Fla.*P=0.002; P=0.007; P=0.0001.

Benefits of Hypolipidemic Treatment% Reduction in Risk of Cardiac End Points0%20%40%70%1013263560LRC-CPPTWOSCOPS4S?% LDL-C Reduction

Chemical Structure of Atorvastatin

Cholesterol Biosynthesis PathwayHMG-CoAreductaseSqualenesynthaseAcetylCoAHMG-CoAMevalonateFarnesylpyrophosphateSqualeneCholesterolFarnesylatedproteinsDolicholE,E,E-GeranylgeranylpyrophosphateGeranylgeranylatedproteinsUbiquinonesRasproteinFarnesyl-transferase

Mechanism of Action of Atorvastatin Conclusions Based on Animal StudiesAuerbach BJ et al. Atherosclerosis. 1995;115:173-180. Krause BR. Newton RS. Atherosclerosis. 1995;117:237-244.EH rabbits:LDL productionEHT rats:VLDL productionGuinea pigs:LDL productionAtorvastatin inhibits hepatic production of major apo B-containing lipoproteins as shown in these animal models

Atorvastatin Clinical Development

Atorvastatin Dose-Response StudyNawrocki JW et al. Arterioscler Thromb Vasc Biol. 1995;15:678-682.Mean Percent Change in LDL-C at 6 Weeks%7.641445061Placebo10 mg20 mg40 mg80 mg*****P

Bakker-Arkema RG et al. JAMA. 1996;275:128-133, and data on file, Parke-Davis (981-38).Atorvastatin in Hypertriglyceridemia56 hypertriglyceridemic patients, 26-74 y/o4-week, randomized, double-blind, placebo-controlled, parallelAtorvastatin 5, 20, 80 mgMean baseline LDL-C: 119 mg/dL (3.1 mmol/L)Mean baseline TG: 603 mg/dL (6.8 mmol/L)Mean baseline HDL-C: 32 mg/dL (0.8 mmol/L)Design and Baseline Lipids

Atorvastatin in HypertriglyceridemiaMean Percent Change in Lipids at 4 Weeks*P

Atorvastatin vs Lovastatin Mean Percent Change in Lipids at 16 WeeksBakker-Arkema RG et al. Atherosclerosis. 1996, and data on file, Parke-Davis (981-08). 1745**VLDL-C6 174**TG* 361 27*LDL-CPlaceboAtorvastatin 10 mgLovastatin 20 mg* 27119*Total-C771*HDL-C* 283 20*Apo B*P0.05 vs atorvastatin.

Atorvastatin vs Pravastatin

Egros F et al. Atherosclerosis. 1996, and data on file, Parke-Davis (981-09).Mean Percent Change in Lipids at 16 WeeksAtorvastatin 10 mgPravastatin 20 mgHDL-CTotal-C*LDL-C*Apo B*TG**P0.05.

Bracs P et al. Atherosclerosis. 1996, and data on file, Parke-Davis (981-37).Atorvastatin vs SimvastatinMean Percent Change in Lipids at 16 WeeksAtorvastatin 10 mgSimvastatin 10 mgHDL-C77Total-C2924*Apo B3430LDL-C3730**-23TG1523**P0.05.

Mean Percent Reduction in LDL-C in Fredrickson Type II Patients in Five Clinical Trials40 mg50981-0420 mg4445981-04981-0710 mg394135981-04981-13981-4380 mg5761981-04981-44Atorvastatin Dose%Reductionin LDL-CBlack DM. Intl Congress Series No. 1066. 1995:307-310, and data on file, Parke-Davis.

Atorvastatin: LDL-C Reduction vs Other StatinsAdapted from Black DM. Intl Congress Series No. 1066. 1995:307-310.

Total-C*45Atorvastatin in Heterozygous FH PatientsMarais AD et al. Atherosclerosis. 1994;109:316.Percent Change in Lipids at 6 WeeksLDL-C*57HDL-C*25TG34%*P

Atorvastatin Efficacy in Homozygous FHMarais AD et al. 12th DALM Symposium; Nov 7-10, 1995; Houston, Tex.Receptor Negative (N=2)Baseline LDL-C: 498 mg/dL (12.9 mmol/L)PercentReductionin LDL-C3Receptor Defective (N=6)Baseline LDL-C: 521 mg/dL (13.5 mmol/L) 223517AtorvastatinSimvastatin

Atorvastatin in Postmenopausal WomenHeinonen T et al. Atherosclerosis. 1996.75Mean Percent Change in Lipids at 12 Weeks4346*9LDL-CPlaceboAtorvastatin 10 mgPlacebo + Estradiol 1 mgAtorvastatin 10 mg + Estradiol 1 mg Total-C133130HDL-C161142TG9*P

Best JD et al. Atherosclerosis. 1994;109:312, and data on file, Parke-Davis (981-13).*P

Titrate to LDL-C 100 mg/dL2.6 mmol/LPrimary: incidence rate of ischemic events, time to ischemic eventSecondary:all-cause mortality, lipid profile, angina classification, QOLEconomic assessment of outcomesLDL-C 130 mg/dL (3.4 mmol/L)TG 400 mg/dL (4.5 mmol/L)Asymptomatic to moderately symptomatic1 lesion 50%-90% stenosisEfficacy ParametersPatient Population (N=320):Recanalization ProcedureAtorvastatin 80 mg/d018UsualCare+MonthAtorvastatin Medical Therapy vs Recanalization (AVERT)McCormick L et al. Atherosclerosis. 1996, and data on file, Parke-Davis (981-68).

Atorvastatin Safety SummaryAdministered to >3000 participants in clinical trials worldwide3 serious adverse events possibly attributable to atorvastatin have been reportedALT elevations >3x ULN:

Atorvastatin: ConclusionsAtorvastatin has a positive dose-response relationship over the range of 10-80 mgLDL-C reductions from 40% to 60%Effective in the broadest range of patients, including hypercholesterolemia, mixed dyslipidemia, hypertriglyceridemia, and homozygous FHSafe and well tolerated in studies up to 2 years